The objective of this Fast-Track program is to develop a novel, stable non-aqueous glucagon formulation with an infusion pump system in closed-loop with continuous glucose monitoring, for treatment of post-bariatric surgery patients who have experienced repetitive severe postprandial hypoglycemia. This approach will provide: (a) automated or semi-automated glucagon; (b) personalized dosing that will not trigger hyperglycemia; and (c) provide a more economical treatment strategy. In this patient population, eating to correct hypoglycemia can actually trigger another subsequent hypoglycemic event, whereas glucagon acts to increase blood glucose levels without triggering excess insulin secretion. Thus there is an urgent need for improved approaches for the treatment of severe hypoglycemia to maintain health, allow optimal nutrition, and improve safety in patients with post-bariatric hypoglycemia (PBH) syndrome. The primary objective of the current proposal is directly relevant to the NIDDK research priorities for obesity treatment and prevention, as well as type 2 diabetes treatment. The Phase I effort of this project will develop algorithms using CGM information to trigger real-time alerts in the presence of hypoglycemia using an automated trigger algorithm that will deploy and deliver a dose of soluble glucagon from a pump, and test this proof-of-concept (POC) in a clinical setting. The Phase II effort of this program will take th optimized algorithm from Phase I into a closed-loop pump system for use in a randomized, blinded, placebo-controlled clinical trial. The data generated in the project may also enable future outpatient studies in which patients can test the system in real-life situations. We propose that the resulting closed-loop glucagon (CLG) system with Xeris' glucagon in an OmniPod(r) will be a more effective treatment for PBH syndrome.